Research has shown that mental disorders co-occur with serious medical illnesses more often than expected by chance alone. The goal of this application is to explore the prospective relationship between depression (both Major Depressive Disorder and depression syndrome) and comorbid metabolic dysregulation as measured by Type 2 Diabetes (and its complications) and Osteoporosis, and to evaluate potential mediators of these relationships. The three aims of the analysis are to (1) use survival analysis to examine the effect of depression on the incidence of the outcomes, (2) create a latent variable model of metabolic dysregulation and evaluate its utility as a mediator of the relationships between depression and Diabetes and Osteoporosis, and (3) investigate the moderating effects of covariates on these relationships, including polymorphisms of the tyrosine hydroxylase gene. The ECA Study recently completed its 23-year follow-up and provides a unique opportunity for exploring these questions. Depression is associated with significant functional impairment in and of itself, and thus it is crucial to identify mechanisms linking it to later debilitating medical illnesses in order to identify targets for intervention to reduce subsequent burdens on affected individuals.